Age-related macular degeneration (AMD) is the most common cause of severe visual loss in the United States and western Europe in people over 55 years of age. The pathogenesis of this disease is poorly understood, and its treatment is limited to laser photocoagulation of neovascular membranes that occur in a subset of individuals with the disease. A number of autosomal dominant maculopathies have been recognized that share some clinical and histopathological features with AMD. Best's disease, the pattern dystrophies, and dominant drusen are each associated with: 1) accumulations of yellow material at the interface of Bruch's membrane and the retinal pigment epithelium (RPE), 2) an increased incidence of choroidal neovascularization, and 3) geographic atrophy of the RPE and photoreceptors in later stages of disease. The similarity between typical AMD and these autosomal dominant maculopathies raises the possibility that AMD is itself an autosomal dominant condition, perhaps even an allelic variant of one of the recognized hereditary maculopathies. Even if typical AMD is a polygenic or multifactorial disease, it is likely to share some pathogenic elements with the clinically similar Mendelian macular dystrophies. The broad objective of this project is to define some of the molecular mechanisms of visual loss in typical age related macular degeneration. Molecular genetic techniques will be used to study large families affected with Best's disease, the pattern dystrophies, and other dominant maculopathies in an effort to map the chromosomal location of the causative genes by linkage analysis. Patients with typical AMD will be studied by segregation analysis for evidence of autosomal dominant inheritance, and affected sib-pair linkage analysis will be used in an attempt to map the chromosomal location of this putative AMD gene. The hypothesis of an allelic relationship between typical AMD and the autosomal dominant maculopathies can then be tested directly. Retinal pigment epithelial cells from normal cadavers, donors with AMD, and rare donors affected with autosomal dominant macular dystrophies, will be cultured. These cells will be studied by 2-D gel electrophoresis to provide a well characterized system of living cells for the future investigation of biochemical mechanisms of disease that are suggested by the linkage analysis portion of the project. The specific aims of the project are to: 1) Map the chromosomal location of the causative mutation of one or more of the autosomal dominant macular dystrophies and test additional pedigrees from Iowa and neighboring institutions for evidence of heterogeneity at these loci. 2) Determine whether age related macular degeneration is frequently caused by a single dominant gene, and if so, map the chromosomal location of this gene. 3) Characterize the two dimensional protein map of normal and abnormal human retinal pigment epithelium cells cultured in our laboratory, to establish a basis for future investigation of the molecular mechanisms of visual loss in AMD and the autosomal dominant maculopathies.